What medication should be started after discontinuing metformin (biguanide) in a patient with type 2 diabetes?

Starting Medication After Discontinuing Metformin in Type 2 Diabetes

When discontinuing metformin in a patient with type 2 diabetes, start an SGLT2 inhibitor as first-line replacement therapy if eGFR ≥30 mL/min/1.73 m², or a GLP-1 receptor agonist if SGLT2 inhibitors cannot be used. 1, 2

Primary Replacement: SGLT2 Inhibitors

SGLT2 inhibitors are the preferred first-line alternative to metformin based on the most recent KDIGO 2020 guidelines, which provide a Grade 1A recommendation for patients with eGFR ≥30 mL/min/1.73 m². 1, 2 These agents offer:

• 31% reduction in cardiovascular death or heart failure hospitalization and 20% reduction in major adverse cardiovascular events, independent of metformin use 2
• Direct renal protective effects including reduced intraglomerular pressure, decreased albuminuria, and slowed GFR decline through mechanisms independent of glycemic control 1
• No risk of hypoglycemia when used as monotherapy 1
• Neutral to modest weight loss effects 1

Critical contraindication: SGLT2 inhibitors must be discontinued when eGFR falls below 30 mL/min/1.73 m² 1

Secondary Replacement: GLP-1 Receptor Agonists

If SGLT2 inhibitors cannot be used, initiate a long-acting GLP-1 receptor agonist (Grade 1B recommendation from KDIGO). 1, 2 These agents provide:

• 22-36% reduction in new or worsening nephropathy with particularly strong benefits when eGFR <60 mL/min/1.73 m² 2
• Cardiovascular mortality reduction comparable to SGLT2 inhibitors 2
• Significant weight loss benefit 1, 2
• Direct renal protective effects independent of glycemic control 1

Context-Specific Considerations

If Metformin Discontinued Due to Renal Impairment (eGFR <30 mL/min/1.73 m²):

Start insulin therapy as the primary option, as both metformin and SGLT2 inhibitors are contraindicated at this level of renal function. 1, 3 GLP-1 receptor agonists remain an option and should be strongly considered before insulin. 1

If Metformin Discontinued Due to Hepatic Impairment:

Consider GLP-1 receptor agonists as the preferred alternative once liver function stabilizes, as they do not carry the same hepatic contraindications as metformin. 4 Metformin may be reconsidered only if liver enzymes and bilirubin return to normal baseline, the underlying cause is identified and resolved, and there is no evidence of cirrhosis. 4

If Patient Has Established Cardiovascular Disease:

Both SGLT2 inhibitors and GLP-1 receptor agonists receive Class IA recommendations from the European Society of Cardiology for patients with established cardiovascular disease or high/very high cardiovascular risk. 2 In this population, these agents should be prioritized over traditional alternatives like sulfonylureas or thiazolidinediones.

Traditional Alternatives (Lower Priority)

If neither SGLT2 inhibitors nor GLP-1 receptor agonists can be used, consider these options in descending order of preference:

• DPP-4 inhibitors: Neutral weight effect, low hypoglycemia risk, but less robust cardiovascular and renal benefits 1
• Sulfonylureas: Effective for glycemic control but carry hypoglycemia risk and weight gain 1, 5
• Thiazolidinediones (pioglitazone): Effective for glycemic control but cause weight gain and fluid retention 1, 6
• Basal insulin: Reserved for patients with severe hyperglycemia (A1C ≥10% or glucose ≥300 mg/dL) or when eGFR <30 mL/min/1.73 m² 1

Critical Pitfalls to Avoid

Do not delay intensification of therapy. The 2018 ADA guidelines explicitly state that drug intensification, including consideration of insulin therapy, should not be delayed in patients not achieving glycemic goals. 1

Do not use GLP-1 receptor agonists and DPP-4 inhibitors together, as they work through similar mechanisms and should not be prescribed in combination. 1

Monitor eGFR closely when initiating SGLT2 inhibitors, as they must be discontinued if eGFR falls below 30 mL/min/1.73 m². 1, 3

Treatment Algorithm

1. Assess eGFR and cardiovascular status before selecting replacement therapy 1, 2
2. If eGFR ≥30 mL/min/1.73 m²: Start SGLT2 inhibitor as first choice 1, 2
3. If SGLT2 inhibitor contraindicated or not tolerated: Start GLP-1 receptor agonist 1, 2
4. If eGFR <30 mL/min/1.73 m²: Consider GLP-1 receptor agonist first, then insulin if needed 1
5. Evaluate HbA1c after 3 months and proceed to combination therapy if targets not achieved 2